Parabens are esters of para-hydroxybenzoic acid. They are used primarily for their bactericidal and fungicidal properties. Examples of parabens include methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, isopropylparaben, benzylparaben and their salts. Because of their low costs, long history of safe use and the inefficacy of natural alternatives, parabens are widely used as preservatives in the cosmetic and pharmaceutical industries. See Darbre et al., 24 J. Appl. Toxicol. 5-13 (2004) and references therein.
Carbomer is a generic name of Carbopol®, a trademarked product from Lubrizol. Carbomer and Carbopol® are used interchangeably in the present application, referring to a synthetic polymer of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol. It can be a homopolymer of acrylic acid, cross-linked with an allyl ether pentaerythritol, allyl ether of sucrose, or allyl ether of propylene. Carbomers have been used as vehicles for drug delivery. They have a long history of safe and effective use in topical gels, creams, lotions, and ointments, as supported by extensive toxicology studies. They have been shown to have extremely low irritancy properties and are non-sensitizing with repeat usage. Carbomers or carbomer copolymers have been used in topical formulations, e.g., for thickening, emulsifying or suspending.
Brimonidine is a selective alpha-2-adrenergic agonist. It has been used as either monotherapy or as adjunctive therapy to lower intraocular pressure (IOP) in the treatment of glaucoma and ocular hypertension (OHT) since its approval in 1996. Brimonidine has also been found to be useful in treating various skin disorders, such as rosacea, erythema caused by rosacea, see, e.g., U.S. Ser. No. 10/853,585 to DeJovin et al.; U.S. Ser. No. 10/626,037 to Scherer; U.S. Ser. No. 12/193,098 to Theobald et al.; telangiectasias, see, e.g., U.S. Patent Application Publication No. 2006/0264515. Topical gel compositions comprising brimonidine, carbomer and paraben(s) for the treatment of skin disorders have been described, see for example, U.S. Ser. No. 10/853,585 to DeJovin et al.; U.S. Ser. No. 12/193,098 to Theobald et al., etc.
In the present invention, crystalline particles of methylparaben have been unexpectedly observed in some brimonidine topical gel formulations and placebo formulations containing carbomer and methylparaben.
There is a need for a topical gel composition containing carbomer and methylparaben that is substantially free of paraben crystalline particles and meets the antimicrobial requirement over an extended period of storage. Such compositions and related methods and products are described in the present application.